Defining the genotypic and phenotypic spectrum of X-linked MSL3 -related disorder,Genetics in Medicine

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Defining the genotypic and phenotypic spectrum of X-linked MSL3 -related disorder
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-11-11 , DOI: 10.1038/s41436-020-00993-y
Theresa Brunet ₁ , Kirsty McWalter ₂ , Katharina Mayerhanser ₁ , Grace M Anbouba ₃ , Amy Armstrong-Javors ₄ , Ingrid Bader ₅ , Evan Baugh ₆ , Amber Begtrup ₂ , Caleb P Bupp _{7,

8} , Bert L Callewaert _{9,

10} , Anna Cereda ₁₁ , Margot A Cousin _{12,

13} , Juan C Del Rey Jimenez ₁₄ , Laurie Demmer ₁₅ , Nikita R Dsouza ₁₆ , Nicole Fleischer ₁₇ , Ralitza H Gavrilova _{12,

18,

19} , Sumedha Ghate ₂₀ , Elisabeth Graf ₂₁ , Andrew Green ₂₂ , Sarah R Green ₂₃ , Maria Iascone ₂₄ , Ameni Kdissa ₂₅ , Dirk Klee ₂₆ , Eric W Klee _{12,

13,

18} , Emily Lancaster ₂₇ , Kristin Lindstrom ₂₈ , Johannes A Mayr ₂₉ , Meriel McEntagart ₃₀ , Naomi J L Meeks ₃₁ , Dana Mittag ₁₅ , Harrison Moore ₃₂ , Anne K Olsen ₃₃ , Damara Ortiz ₂₇ , Gretchen Parsons ₇ , Loren D M Pena _{34,

35} , Richard E Person ₂ , Sumit Punj ₂ , Gonzalo Alonso Ramos-Rivera ₃₆ , Maria J Guillen Sacoto ₂ , G Bradley Schaefer ₂₃ , Rhonda E Schnur ₂ , Tiana M Scott _{37,

38} , Daryl A Scott _{37,

39,

40} , Carolyn R Serbinski ₃₄ , Vandana Shashi ₄₁ , Victoria M Siu ₄₂ , Barbro Fossøy Stadheim ₄₃ , Jennifer A Sullivan ₄₁ , Jana Švantnerová ₄₄ , Lea Velsher ₄₅ , David S Wargowski _{3,

20} , Ingrid M Wentzensen ₂ , Dagmar Wieczorek ₄₆ , Juliane Winkelmann _{1,

47,

48,

49} , Patrick Yap _{50,

51} , Michael Zech _{1,

47} , Michael T Zimmermann _{16,

52,

53} , Thomas Meitinger ₁ , Felix Distelmaier ₅₄ , Matias Wagner _{1,

47}

Affiliation

Institute of Human Genetics, Technical University Munich, Munich, Germany.
GeneDx, Inc., Gaithersburg, MD, USA.
Division of Genetics and Metabolism, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Pediatric Neurology, Massachusetts General Hospital, Boston, MA, USA.
Department of Clinical Genetics, University Children's Hospital, Paracelsus Medical University, Salzburg, Austria.
Institute for Genomic Medicine, Columbia University, New York, NY, USA.
Medical Genetics, Spectrum Health and Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Department of Pediatrics, ASST Papa Giovanni XXIII, Bergamo, Italy.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
St George's Genomics Service, St George's University Hospitals NHS FT, London, UK.
Medical Genetics, Atrium Health Levine Children's Hospital, Charlotte, NC, USA.
Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA.
FDNA Inc., Boston, MA, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
St Vincent Hospital Medical Genetics Clinic, Green Bay, WI, USA.
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland.
University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Springdale, AR, USA.
Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
CENTOGENE AG, Rostock, Germany.
Department of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.
Department of Pediatrics, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria.
Medical Genetics, St George's University Hospitals NHS FT, London, UK.
Department of Pediatrics, Section of Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
INTEGRIS Pediatric Specialties/Medical Genetics, Oklahoma City, OK, USA.
Department of Pediatric, Soerlandet Sykehus Kristiansand, Kristiansand, Norway.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Department of Pediatric Neurology, National Institute of Children's Diseases, Bratislava, Slovakia.
Texas Children's Hospital, Houston, TX, USA.
Department of Microbiology and Molecular Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.
Department of Pediatrics, Western University, London, ON, Canada.
Department of Clinical Genetics, Oslo University Hospital, Oslo, Norway.
Second Department of Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava, Bratislava, Slovakia.
Genetics Program, North York General Hospital, Toronto, ON, Canada.
Institute of Human Genetics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Neurogenetics, Technische Universität München, Munich, Germany.
Genetic Health Service New Zealand (Northern Hub), Auckland, New Zealand.
Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, Heinrich-Heine-University, Düsseldorf, Germany.

Purpose

We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome).

Methods

Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers.

Results

We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined.

Conclusion

Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata–Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

中文翻译：

定义 X 连锁 MSL3 相关疾病的基因型和表型谱

目的

我们试图描绘患有 X 连锁MSL3相关疾病（Basilicata-Akhtar 综合征）的女性和男性个体的基因型和表型谱。

方法

在 10 个不同的测序中心通过外显子组或基因组测序确定了 25 名具有MSL3致病变异的个体（15 名男性，10 名女性）。

结果

我们在MSL3中鉴定了多种变体类型（十个无意义、六个移码、四个剪接位点、三个错义、一个框内缺失、一个多外显子缺失），大多数被证明是从头发生的，并且在末端八个外显子中聚集表明前五个外显子中的截断变体可能会被替代MSL3补偿成绩单。错义和剪接变体的三维建模表明这些具有有害影响。主要临床发现包括发育迟缓和智力障碍，范围从轻度到重度。自闭症谱系障碍、肌张力异常和大头畸形以及听力障碍和胃肠道问题很常见。小脑蚓部发育不全作为一致的磁共振图像 (MRI) 发现出现。女性和男性同样受到影响。使用面部分析技术，确定了可识别的面部格式塔。